Role of oligodendrocyte precursor cell-endothelial tip cell interactions in white matter development and repair

In the central nervous system (CNS), commencement of myelination begins with oligodendrocyte precursor cells (OPCs) differentiating into mature oligodendrocytes (OLs) that produce myelin. During myelination, OPCs undergo a 6500-fold membrane expansion and substantial proteolipid synthesis. This requires significant metabolic resources, which are met by a complex cerebrovascular network that supply OPCs with metabolites and oxygen. The cerebrovascular network is formed through sprouting angiogenesis, growth of new blood vessels from existing vasculature, led by endothelial tip cells. Endothelial tip cells are specialized migrating cells, and are highly glycolytic to meet their metabolic demands associated with rapid remodelling of their cytoskeleton to migrate and fuse with the neighboring tip cells to form functionally perfused blood vessels. Notably, during postnatal development the timecourses for commencement of myelination and sprouting angiogenesis overlap. This raises the possibility for metabolic coordination between these processes. However, our understanding of how oligodendrocyte lineage cells interact with the vasculature remains incomplete. We know that OPC interact physically with endothelial tip cells. My preliminary data shows hypoxia inducible factor (HIF) activity within OPCs promotes endothelial tip cell-Glut1 expression and neoangiogenesis. Genetically blocking Glut1 within CNS endothelium specifically also caused myelination deficits. These findings support my central hypothesis that OPC-intrinsic HIF signaling regulates endothelial tip cell-Glut1 mediated glucose uptake, which metabolically supports vascularization and myelination during development and promotes repair post neonatal hypoxic brain injury. I will test this hypothesis in the following aims: For my first aim, I will utilize OPC-intrinsic HIF mutant mouse models alongside ex vivo slice cultures, immunohistochemical (IHC), electron microscopy (EM) and smFISH analysis to characterize changes in OPC-vascular and endothelial tip cell interactions and tip cell-Glut1 levels and cortical and white matter glucose levels. For my second aim, I will employ a tip cell-specific Glut1 conditional knockout model, along with laser speckle contrast imaging and compound actional potential recording techniques to understand how cerebral vascularization, blood flow and myelination are functionally regulated through glucose mediated metabolic support in normal development and after hypoxic injury. These powerful models and combinatorial use of in vivo and ex vivo approaches outlined in this study will shed light on the metabolic crosstalk between OPCs and endothelial tip cells. Project Number: 1F31NS149505-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Isa Maxwell | Institution: OREGON HEALTH & SCIENCE UNIVERSITY, PORTLAND, OR | Award Amount: $50,114 | Activity Code: F31 | Study Section: Special Emphasis Panel[ZRG1 F01A-N (20)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11387116